Opiates interfere with endocrine activities essential to normal sexual function. Impotence, sterility and diminished libido are recognized clinical phenomena associated with chronic opiate abuse. Opiate induced perturbations of hypothalamic-pituitary function may be involved in addictive behavior and changes in mood states. Further investigations on the biochemical mechanisms underlying the neuroendocrine effects of opiates are proposed. We have demonstrated in man that acute and chronic use of opiates lowers plasma testosterone levels. Acute opiate administration probably inhibits hypothalamic secretion of luliberin as indicated by a rapid suppression of lutropin release, a subsequent drop in plasma testosterone levels, and a normal lutropin response to luliberin administration before or after an opiate. Naltrexone (a long-acting narcotic antagonist) not only blocks this inhibitory effect of opiates, but by itself increases the frequency of lutropin secretory pulses and the mean plasma lutropin level. Protracted supersensitivity to the lutropin stimulation effect of naltresone is indicated in ex-addicts. These findings suggest that endogenous opioid mechanisms are improtant to normal hypothalamic-pituitary function, that narcotic drugs suppress central regulatory mechanisms, and that long-term neuroendocrine changes may result from chronic opiate abuse. Experiments in vivo with catheterized rats are proposed for assessment of opiate effects on the episodic pulsatile release of pituitary, gonadal and adrenocortical hormones. Integrated blood samples will be collected for hormone radioimmunoassay. These studies are designed to elucidate the endocrine site(s) and mechanism of opiate action in the whole animal using procedures that are not feasible with man. Experiments in vitro, with preparations of hypothalamic, pituitary and gonadal tissues, will be conducted to investigate the biochemical mechanisms underlying opiate effects. Pilot studies are described and preliminary evidence is presented that supports hypotheses suggested by our clinical findings.